2. Academic Validation
  3. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia

XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia

  • Nature. 2017 Jan 5;541(7635):87-91. doi: 10.1038/nature20790.
Nicolas C Hoch 1 2,  Hana Hanzlikova 1,  Stuart L Rulten 1,  Martine Tétreault 3,  Emilia Komulainen 1,  Limei Ju 1,  Peter Hornyak 1,  Zhihong Zeng 1,  William Gittens 1,  Stephanie A Rey 4,  Kevin Staras 4,  Grazia M S Mancini 5,  Peter J McKinnon 6,  Zhao-Qi Wang 7,  Justin D Wagner 8,  Care4Rare Canada Consortium,  Grace Yoon 9,  Keith W Caldecott 1
Affiliations

Affiliations

  • 1 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.
  • 2 CAPES Foundation, Ministry of Education of Brazil, Brasilia/DF 70040-020, Brazil.
  • 3 Department of Human Genetics, McGill University and Genome Québec Innovation Centre, Montréal, Québec, H3A 0G4, Canada.
  • 4 Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK.
  • 5 Department of Clinical Genetics, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
  • 6 St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
  • 7 Leibniz Institute for Age Research, Fritz Lipmann Institute, 1107745 Jena, Germany.
  • 8 The Children's Hospital of Eastern Ontario Research Institute, Ottawa, K1L 8H1, Canada.
  • 9 Division of Clinical and Metabolic Genetics, and Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, M5G 1X8, Canada.
PMID: 28002403 DOI: 10.1038/nature20790
Abstract

XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of PARP1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.

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